CN102382118A - Preparation method of 7alpha-acetyl-6,14-ethyl bridge tetrahydrothebaine - Google Patents
Preparation method of 7alpha-acetyl-6,14-ethyl bridge tetrahydrothebaine Download PDFInfo
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Abstract
The invention relates to the field of the double bond hydrogenation reaction of a thenorphine intermediate, in particular to a preparation method of 7alpha-acetyl-6,14-ethyl bridge tetrahydrothebaine. The method comprises the following steps of: dissolving 7alpha-acetyl-6,14-ethylene bridge tetrahydrothebaine serving as a raw material into a polar solvent; adding an effective quantity of catalyst and organic alkaline reagent; and introducing an excessive amount of hydrogen at certain temperature and under certain pressure for undergoing a hydrogenation reduction reaction to obtain 7alpha-acetyl-6,14-ethyl bridge tetrahydrothebaine, wherein the polar solvent is absolute ethyl alcohol or absolute methanol; the catalyst is palladium carbon or platinum dioxide; the organic alkaline reagent is pyridine; and the using amount of the organic alkaline reagent is 1-5 percent (v/w) based on the amount of the 7alpha-acetyl-6,14-ethylene bridge tetrahydrothebaine. The method disclosed by the invention has the advantages of high operating safety, high product yield and low production cost.
Description
Technical field
The present invention relates to thiophene promise coffee intermediate double key hydrogenation reaction field, be specifically related to a kind of 7 ɑ-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine.
Background technology
Thi ophene hydrochloride promise coffee, English Thenorphine Hydrochloride by name,
Chemistry 21-Cyclopropyl-7 α by name-[1-(R)-1-hydroxy-1-methyl-3-(thien-2-yl) propyl]-6,14endoethano-6,7,8,14-tetrahydrooripavine Hydrochloride Monohydrate.Structural formula:
Thi ophene hydrochloride promise coffee is that Poison & Medicine Inst. of Military Medicial Sciences Academy develops voluntarily, has the first class national new drug of independent intellectual property right, and this medicine novel structure is the opiate receptor partial agonist.Pharmacodynamic study shows that this medical instrument has analgesia usefulness strong, long action time, and effective dose is little; Oral absorption is good, no drug dependence potential, and acute toxicity is little; Advantages such as SF is big are compared with present clinical widely used buprenorphine, and analgesia usefulness is strong; And drug dependence is little, and this medicine antagonism morphineation is remarkable, might become one and take into account the anodyne of high-efficiency low-toxicity and preventing suction again medicine safely and effectively.
The hydrogenation reduction method of existing thi ophene hydrochloride promise coffee midbody is through the logical hydrogen addition of high pressure 4-5MPa (referring to CN01142149.5) catalysis, and is high to equipment requirements, has high input; And product yield is low; Inconvenient operation, problems such as poor stability, and also yield is about 75%.
Summary of the invention
Shortcoming and defect to above-mentioned prior art existence; The object of the invention aims to provide a kind of reduction reaction of double-bond hydrogenation safely and efficiently method; Specifically provide 7 ɑ-ethanoyl-6 that a kind of production operation condition safety is gentle, feed stock conversion is high, by product is few, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine.
For realizing goal of the invention of the present invention, the contriver provides following technical scheme:
A kind of 7 ɑ-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine comprises the steps:
With 7 ɑ-ethanoyl-6; 14-etheno tetrahydrochysene thebaine is a raw material, and material dissolution in the polarity solvent, is added the catalyzer and the organic basic reagent of significant quantity; Under certain temperature and pressure, feeding excess hydrogen carries out hydrogenation reduction and makes 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine, wherein, described polarity solvent is selected absolute ethyl alcohol or anhydrous methanol for use; Catalyzer is palladium carbon or platinum dioxide; Organic basic reagent is pyridine, and its consumption is 7 ɑ-ethanoyl-6, the 1-5% (v/w) of 14-etheno tetrahydrochysene thebaine.
Preparing method's of the present invention reaction formula is:
With thiophene promise coffee midbody 7 ɑ-ethanoyl-6; 14-etheno tetrahydrochysene thebaine is dissolved in the absolute ethyl alcohol (or methyl alcohol), adds palladium catalyst carbon (or platinum dioxide), adds organic basic reagent pyridine again; System is after ventilation; Under certain temperature and pressure, feed hydrogen and carry out hydrogenation reduction, process the hydrogenation thing.Preparing method of the present invention has selected the anti-poisoning reagent of pyridine as palladium catalyst carbon or platinum dioxide; The existence of pyridine can with some acid halogen ionizations; The catalytic capability that has not only kept palladium carbon or platinum dioxide; Reduced the by product generation simultaneously, the hydrogenation reaction time has also been shortened in the maintenance of catalyst activity.Simultaneously the total recovery of hydrogenation reduction process is near theoretical yield, and with the high pressure shortening relatively, yield rises to about 98% from 75%, and product HPLC content reaches more than 98.5%.
As preferably, according to a kind of 7 ɑ of the present invention-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine, wherein, the said temperature that under certain temperature and pressure, is meant is 50-60 ℃, pressure is 0.01-0.1MPa.Reaction can be carried out smoothly, and feed stock conversion is high, and by product is few.Low pressure shortening technology also greatly reduces the potential safety hazard in the operation, has simplified operation.
As preferably, according to a kind of 7 ɑ of the present invention-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine, wherein, the time that said feeding excess hydrogen is carried out hydrogenation reduction is 8-12 hour.React completely, and can fine control production cost.
As preferably, according to a kind of 7 ɑ of the present invention-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine, wherein, and with 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine weight meter, catalyst consumption is 20-60%.Satisfy reaction requirements, rationally controlled production cost, avoided unnecessary waste.
As preferably, according to a kind of 7 ɑ of the present invention-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine, wherein, described material dissolution makes material concentration be controlled between the 7%-10% (w/v) in the polarity solvent.Concentration is crossed low or too high, all is unfavorable for reacting carrying out, and concentration is crossed low reaction speed and slowed down, easy analysis of material of excessive concentration or post-processing operation inconvenience.
As preferably, according to a kind of 7 ɑ of the present invention-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine; Wherein, described hydrogenation reduction also comprises after finishing: earlier hydrogenation reduction liquid is carried out heat filtering, use the washing with alcohol filter cake again; The gained filtrate decompression concentrates and obtains enriched product (near doing), and enriched product adds and is equivalent to 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine charging capacity 0.5-1.0 ethanol doubly; Be cooled to 5 ℃ after waiting to stir again; Leave standstill more than 4 hours centrifugally, centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is 1 times also dries; The most rearmounted 60 ℃ of oven dry obtain 7 ɑ-ethanoyl-6,14-ethyl bridge tetrahydrochysene thebaine product.To the aftertreatment of hydrogenation reduction product, can make title product 7 ɑ-ethanoyl-6,14-ethyl bridge tetrahydrochysene thebaine yield optimization, and the title product purity that obtains is also than higher, and HPLC purity is more than 98.5% usually.
Compared with prior art, the present invention has following advantage:
The present invention adopts absolute ethyl alcohol or anhydrous methanol to make solvent, and in the presence of pyridine, temperature of reaction is about 56 ℃; Through palladium carbon or platinum dioxide catalytic hydrogenation reaction, total recovery can reach about 98% pressure at 0.01MPa-0.1MPa, and HPLC content reaches more than 98.5%; Wherein the existence of pyridine can with some acid halogen ionizations, avoid palladium carbon or platinum dioxide because of the poisoning inactivation, the hydrogenation reaction time has been shortened in the maintenance of catalyst activity; And by product obviously reduces, with the high pressure shortening more not only yield rise to about 98% from 75%, and processing safety promotes greatly; Be a kind of environmental protection technology, be worth promoting.
It is low that the present invention has cost of investment, and equipment interoperability is good, the characteristics of high efficiency.
The improvement of the logical hydrogen methods of the present invention makes that hydrogen can carry out fresh handing-over in the reaction system, plays the effect that improves speed of response.
The present invention adopts the low-voltage equipment hydrogenation reaction, greatly reduces investment of devices cost and maintaining cost.
Application of the present invention reaches about 98% the total recovery of reaction, near theoretical level, raw material resources is fully utilized.
Embodiment
Below in conjunction with embodiment, content of the present invention is described more specifically.Should be appreciated that enforcement of the present invention is not limited to following embodiment, all will fall into protection domain of the present invention any pro forma accommodation and/or the change that the present invention made.
In the present invention, if not refer in particular to, all part, per-cents are weight unit, and all equipment and raw material etc. all can be buied from market or the industry is commonly used.Do not specialize if having, the method that embodiment adopts is this area current techique.
Embodiment 1
In 20L hydrogenation reaction jar, drop into 14L absolute ethyl alcohol and 1Kg thiophene promise coffee midbody 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine adds 10% palladium carbon 0.2Kg and pyridine 50mL again; Open hydrogen to pressure 0.01MPa, system is vacuumized use hydrogen exchange earlier, under logical hydrogen condition; Stirring is warming up to 56 ℃ and carried out hydrogenation reduction 8 hours, and a small amount of fresh hydrogen exchange is arranged during reaction, and the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used washing with alcohol again, and the gained filtrate decompression is concentrated near doing; Enriched product adds and is equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 0.5 times stirs about postcooling to 5 ℃, leaves standstill more than 4 hours centrifugal; Centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is about 1 times also dries, and the most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine product), yield 98%, HPLC content 99.18%.
Embodiment 2
In three mouthfuls of hydrogenation reaction bottles of 500mL, drop into 280mL anhydrous methanol and 20g thiophene promise coffee midbody 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine adds 10% palladium carbon 4g and pyridine 1mL again; Open hydrogen to pressure 0.01MPa, system is vacuumized use hydrogen exchange earlier, under logical hydrogen condition; Stirring is warming up to 56 ℃ of reactions 12 hours, and a small amount of fresh hydrogen exchange is arranged during reaction, and the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used methanol wash again, and the gained filtrate decompression is concentrated near doing; Divide 3 times with the methyl alcohol band to the greatest extent with ethanol again, enriched product adds and is equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 1.0 times stirs about postcooling to 5 ℃; Leave standstill more than 4 hours centrifugally, centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is about 1 times also dries; The most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine product), yield 97%, HPLC content 98.56%.
Embodiment 3
In three mouthfuls of hydrogenation reaction bottles of 500mL, drop into 280mL absolute ethyl alcohol and 20g thiophene promise coffee midbody 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine adds platinum dioxide 2g and pyridine 1mL again; Open hydrogen to pressure 0.01MPa, system is vacuumized use hydrogen exchange earlier, under logical hydrogen condition; Stirring is warming up to 56 ℃ of reactions 12 hours, and a small amount of fresh hydrogen exchange is arranged during reaction, and the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used washing with alcohol again, and the gained filtrate decompression is concentrated near doing; Enriched product adds and to be equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 0.7 times stirs about postcooling to 5 ℃, leaves standstill more than 4 hours centrifugal; Centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is about 1 times also dries, and the most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine product), yield 98%, HPLC content 98.88%.
Embodiment 4
In three mouthfuls of hydrogenation reaction bottles of 1000mL, drop into 750mL absolute ethyl alcohol and 50g thiophene promise coffee midbody 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine adds 10% palladium carbon 10g and pyridine 1mL again; Open hydrogen to pressure 0.01MPa, system is vacuumized use hydrogen exchange earlier, under logical hydrogen condition; Stirring is warming up to 50 ℃ of reactions 10 hours, and a small amount of fresh hydrogen exchange is arranged during reaction, and the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used washing with alcohol again, and the gained filtrate decompression is concentrated near doing; Enriched product adds and is equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 0.5 times stirs about postcooling to 5 ℃, leaves standstill more than 4 hours centrifugal; Centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is about 1 times also dries, and the most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine product), yield 97%, HPLC content 99.2%.
Embodiment 5
In three mouthfuls of hydrogenation reaction bottles of 1000mL, drop into 600mL absolute ethyl alcohol and 50g thiophene promise coffee midbody 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine adds 10% palladium carbon 10g and pyridine 1mL; Open hydrogen to pressure 0.01MPa, system is vacuumized use hydrogen exchange earlier, under logical hydrogen condition; Stirring is warming up to 60 ℃ of reactions 9 hours, and a small amount of fresh hydrogen exchange is arranged during reaction, and the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used washing with alcohol again, and the gained filtrate decompression is concentrated near doing; Enriched product adds and is equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 0.9 times stirs about postcooling to 5 ℃, leaves standstill more than 4 hours centrifugal; Centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is about 1 times also dries, and the most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine product), yield 98.6%, HPLC content 96.62%.
Embodiment 6
In three mouthfuls of hydrogenation reaction bottles of 1000mL, drop into 600mL absolute ethyl alcohol and 50g thiophene promise coffee midbody 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine adds 10% palladium carbon 10g and pyridine 1mL again; Open hydrogen to pressure 0.01MPa, system is vacuumized use hydrogen exchange earlier, under logical hydrogen condition; Stirring is warming up to 56 ℃ of reactions 10 hours, and a small amount of fresh hydrogen exchange is arranged during reaction, and the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used washing with alcohol again, and the gained filtrate decompression is concentrated near doing; Enriched product adds and is equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 1 times stirs about postcooling to 5 ℃, leaves standstill more than 4 hours centrifugal; Centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is about 1 times also dries, and the most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine product), yield 97.8%, HPLC content 99.8%.
Embodiment 7
In three mouthfuls of hydrogenation reaction bottles of 1000mL, drop into 600mL absolute ethyl alcohol and 50g thiophene promise coffee midbody 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine adds 10% palladium carbon 10g and pyridine 1mL again; Open hydrogen to pressure 0.01MPa, system is vacuumized use hydrogen exchange earlier, under logical hydrogen condition; Stirring is warming up to 56 ℃ of reactions 12 hours, and a small amount of fresh hydrogen exchange is arranged during reaction, and the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used washing with alcohol again, and the gained filtrate decompression is concentrated near doing; Enriched product adds and is equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 0.7 times stirs about postcooling to 5 ℃, leaves standstill more than 4 hours centrifugal; Centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is about 1 times also dries, and the most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine product), yield 98.2%, HPLC content 99.85%.
Embodiment 8
In three mouthfuls of hydrogenation reaction bottles of 1000mL, drop into 600mL absolute ethyl alcohol and 50g thiophene promise coffee midbody 7 ɑ-ethanoyl-6; 14-etheno tetrahydrochysene thebaine; Add 10% palladium carbon 20g and pyridine 1mL again, open hydrogen, system is vacuumized use hydrogen exchange earlier to pressure 0.01MPa.Under logical hydrogen condition.Stirring is warming up to 56 ℃ of reactions 8 hours, and a small amount of fresh hydrogen exchange is arranged during reaction, and the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used washing with alcohol again, and the gained filtrate decompression is concentrated near doing; Enriched product adds and to be equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 0.5 times stirs about postcooling to 5 ℃, leaves standstill more than 4 hours centrifugal; Centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6; The about 1 times washing with alcohol of 14-etheno tetrahydrochysene thebaine charging capacity also dries, and the most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6,14-ethyl bridge tetrahydrochysene thebaine product); Yield 97%, HPLC content 99.2%.
Embodiment 9
In three mouthfuls of hydrogenation reaction bottles of 1000mL, drop into 600mL absolute ethyl alcohol and 50g thiophene promise coffee midbody 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine adds 10% palladium carbon 25g and pyridine 1mL again; Open hydrogen to pressure 0.01MPa, system is vacuumized use hydrogen exchange earlier, under logical hydrogen condition; Stirring is warming up to 56 ℃ of reactions 8 hours, and a small amount of fresh hydrogen exchange is arranged during reaction, and the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used washing with alcohol again, and the gained filtrate decompression is concentrated near doing; Enriched product adds and is equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 0.8 times stirs about postcooling to 5 ℃, leaves standstill more than 4 hours centrifugal; Centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is about 1 times also dries, and the most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine product), yield 96.8%, HPLC content 96.74%.
Embodiment 10
In three mouthfuls of hydrogenation reaction bottles of 1000mL, drop into 600mL absolute ethyl alcohol and 50g thiophene promise coffee midbody 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine adds 10% palladium carbon 30g and pyridine 1mL again; Open hydrogen to pressure 0.01MPa, system is vacuumized use hydrogen exchange earlier, under logical hydrogen condition; Stirring is warming up to 56 ℃ of reactions 8 hours, and a small amount of fresh hydrogen exchange is arranged during reaction, and the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used washing with alcohol again, and the gained filtrate decompression is concentrated near doing; Enriched product adds and is equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 0.6 times stirs about postcooling to 5 ℃, leaves standstill more than 4 hours centrifugal; Centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is about 1 times also dries, and the most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine product), yield 96.5%, HPLC content 99.38%.
Embodiment 11
In three mouthfuls of hydrogenation reaction bottles of 1000mL, drop into 600mL absolute ethyl alcohol and 50g thiophene promise coffee midbody 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine adds 10% palladium carbon 10g and pyridine 1.5mL again; Open hydrogen to pressure 0.01MPa, system is vacuumized use hydrogen exchange earlier, under logical hydrogen condition; Stirring is warming up to 56 ℃ of reactions 8 hours, and a small amount of fresh hydrogen exchange is arranged during reaction, and the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used washing with alcohol again, and the gained filtrate decompression is concentrated near doing; Enriched product adds and is equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 1.0 times stirs about postcooling to 5 ℃, leaves standstill more than 4 hours centrifugal; Centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is about 1 times also dries, and the most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine product), yield 99.2%, HPLC content 99.55%.
Embodiment 12
In three mouthfuls of hydrogenation reaction bottles of 500mL, drop into 280mL absolute ethyl alcohol and 20g thiophene promise coffee midbody 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine adds 10% palladium carbon 4g and pyridine 0.5mL again; Open hydrogen to pressure 0.01MPa, system is vacuumized use hydrogen exchange earlier, under logical hydrogen condition; Stirring is warming up to 56 ℃ of reactions 12 hours, and a small amount of fresh hydrogen exchange is arranged during reaction, and the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used washing with alcohol again, and the gained filtrate decompression is concentrated near doing; Enriched product adds and is equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 1.0 times stirs about postcooling to 5 ℃, leaves standstill more than 4 hours centrifugal; Centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is about 1 times also dries, and the most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine product), yield 97.7%, HPLC content 98.76%.
Comparative example 1
In 1000mL hydrogenation autoclave, drop into 280mL absolute ethyl alcohol and 20g thiophene promise coffee midbody 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine adds palladium carbon 4g again; Open hydrogen and boost to 5MPa, stir and be warming up to 56 ℃ of reactions 12 hours, the TLC detection reaction is complete; Earlier hydrogenation reduction liquid is carried out heat filtering, filter cake is used washing with alcohol again, and the gained filtrate decompression is concentrated near doing; Enriched product adds and is equivalent to 7 ɑ-ethanoyl-6, and the ethanol that 14-etheno tetrahydrochysene thebaine charging capacity is 1.0 times stirs about postcooling to 5 ℃, leaves standstill more than 4 hours centrifugal; Centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6; The about 1 times washing with alcohol of 14-etheno tetrahydrochysene thebaine charging capacity also dries, and the most rearmounted 60 ℃ of oven dry obtain hydrogenation thing (i.e. 7 ɑ-ethanoyl-6,14-ethyl bridge tetrahydrochysene thebaine product); Yield 75%, HPLC content 99.12%.
Although the contriver has done comparatively detailed elaboration to technical scheme of the present invention and has enumerated; Be to be understood that; For the those skilled in the art in this area, be obvious to the replacement scheme that the foregoing description modifies, flexible perhaps employing is equal to, all can not break away from the essence of spirit of the present invention; The term that occurs among the present invention is used for can not being construed as limiting the invention the elaboration of technical scheme of the present invention and understanding.
Claims (6)
1. 7 ɑ-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine comprises the steps:
With 7 ɑ-ethanoyl-6; 14-etheno tetrahydrochysene thebaine is a raw material, and material dissolution in the polarity solvent, is added the catalyzer and the organic basic reagent of significant quantity again; Under certain temperature and pressure, feeding excess hydrogen carries out hydrogenation reduction and makes 7 ɑ-ethanoyl-6; 14-ethyl bridge tetrahydrochysene thebaine, wherein, described polarity solvent is selected from absolute ethyl alcohol or anhydrous methanol; Catalyzer is palladium carbon or platinum dioxide; Organic basic reagent is pyridine, and its consumption is 7 ɑ-ethanoyl-6, the 1-5% (v/w) of 14-etheno tetrahydrochysene thebaine.
2. a kind of 7 ɑ as claimed in claim 1-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine is characterized in that, and the said temperature that under certain temperature and pressure, is meant is 50-60 ℃, and pressure is 0.01-0.1MPa.
3. a kind of 7 ɑ as claimed in claim 1-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine is characterized in that the time that described feeding excess hydrogen is carried out hydrogenation reduction is 8-12 hour.
4. a kind of 7 ɑ as claimed in claim 1-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine is characterized in that, with 7 ɑ-ethanoyl-6,14-etheno tetrahydrochysene thebaine weight meter, catalyst consumption is 20-60%.
5. a kind of 7 ɑ as claimed in claim 1-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine is characterized in that described material dissolution makes material concentration be controlled between the 7-10% (w/v) in the polarity solvent.
6. a kind of 7 ɑ as claimed in claim 1-ethanoyl-6, the preparation method of 14-ethyl bridge tetrahydrochysene thebaine is characterized in that; Described hydrogenation reduction also comprises after finishing: at first the product with hydrogenation reduction carries out heat filtering; Use the washing with alcohol filter cake simultaneously, the gained filtrate decompression concentrates and obtains enriched product, and enriched product adds and is equivalent to 7 ɑ-ethanoyl-6; After stirring, 14-etheno tetrahydrochysene thebaine charging capacity 0.5-1.0 ethanol doubly is cooled to 5 ℃ again; Leave standstill more than 4 hours centrifugally, centrifugal product is again with being equivalent to 7 ɑ-ethanoyl-6, and the washing with alcohol that 14-etheno tetrahydrochysene thebaine charging capacity is 1 times also dries; The most rearmounted 60 ℃ of oven dry obtain 7 ɑ-ethanoyl-6,14-ethyl bridge tetrahydrochysene thebaine.
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| CN2011101329949A CN102382118A (en) | 2011-05-23 | 2011-05-23 | Preparation method of 7alpha-acetyl-6,14-ethyl bridge tetrahydrothebaine |
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| CN2011101329949A Pending CN102382118A (en) | 2011-05-23 | 2011-05-23 | Preparation method of 7alpha-acetyl-6,14-ethyl bridge tetrahydrothebaine |
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| CN110615794A (en) * | 2019-09-20 | 2019-12-27 | 甘肃省药物碱厂 | Method for extracting and separating thebaine from poppy shell |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110615794A (en) * | 2019-09-20 | 2019-12-27 | 甘肃省药物碱厂 | Method for extracting and separating thebaine from poppy shell |
| CN110615794B (en) * | 2019-09-20 | 2022-04-19 | 甘肃省药物碱厂 | Method for extracting and separating thebaine from poppy shell |
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